Synthesis of steroids



3,033,910 SYNTHESTS F STEROIDS Josef Fried, New Brunswick, N.J.,assignor to Olin Mathisson Chemical Corporation, New York, N.Y., acorporation of Virginia No Drawing. Filed May 27, 1955, Ser. No. 511,7837 Claims. (Cl. 260-3973) This invention relates to the synthesis ofvaluable steroids.

One of the objects of this invention is the provision of an advantageousprocess of preparing steroids of the pregnane (including allopregnane,pregnene and pregnadiene) series having a 14,15-double bond.

Another object of this invention is the provision of steroids of thepregnane (including allopregnane, pregnene, and pregnadiene) serieshaving a 14,15-double bond, which compounds are useful for their ownphysiological action.

Still another object of this invention is the provision ofl-(organic-sulfonyloxy)-progesterones, useful as intermediates in thepreparation of the 14,15-double-bonded steroids of this invention.

The new steroids of this invention comprise: (a)(organic-sulfonyloxy)-progesterones; (b) l4-dehydroprogesterone; (c)l4-dehydro-allopregnane-3,20-dione; and (d)l4-dehydropregnane-3,20-dione.

The new 14-dehydroprogesterone of this invention may be prepared by aprocess essentially comprising converting either.ISa-hydroxyprogesterone or ISfl-hydroxyprogesterone to the correspondingorganic sulfonate ester to form the novel organic sulfonic acid estersof this invention, and then removing the organic sulfonic acid moiety toform a 14,15-double bond.

The 15-hydroxyprogesterone steroids useful as starting materials in theprocesses of this invention can be prepared by the methods disclosed byJosef Fried et al. in their application, Serial No. 372,798, filedAugust 6, 1953, and now Patent No. 2,753,290, granted July 3, 1956.

The preparation of the organic sulfonic acid esters of the15-hydroxyprogesterones is preferably accomplished by reacting aIS-hydroxyprogesterone with an organic sulfonyl halide (sulfonylchlorides are preferred but other halides such as bromides and iodidesmay be used). Although any organic chloride is utilizable, and suitablereagents include the aliphatic sulfonyl chlorides (e.g. thealkanesulfonyl chlorides) and the aromatic sulfonyl chlorides (e.g. thebenzenesulfonyl chlorides), the preferred sulfonyl chlorides are thosewherein the organic radical is a hydrocarbon of less than nine carbonatoms, as exemplified by the lower alkanesulfonyl chlorides [e.'g.ethanesulfonyl chloride and especially methanesulfonyl chloride (mesylchloride)] and the monocyclic hydrocarbon aromatic sulfonyl chlorides[c.g. benzenesulfonyl chloride and p-toluenesulfonyl chloride (tosylchloride)]. The reaction is carried out in accordance with the generalmethod disclosed in my US. application, Serial No. 417,489, filed March10, 1954; and in the following examples, by reacting thelS-hydroxyprogesterone and sulfonyl halide in the presence of a tertiaryorganic base, such as pyridine. The reaction results in the productionof one of the new intermediates of this invention, a progesterone havingan organic sulfonyloxy radical in the 15-position (alpha or beta,depending on the configuration of the starting 15- hydroxyprogesterone)These intermediates are then reacted with an alkali metal salt of alower fatty acid in a substantially anhydrous liquid lower fatty acid(e. g. sodium acetate in glacial acetic acid, or potassium formate informic acid) to split olf the organic sulfonic acid moiety, therebyforming the l4-dehydroprogesterone of this invention. This conversioncan also be effected by treatment with an alkali metal halide atet ice

(e.g. sodium iodide, potassium iodide or lithium bromide) in an organicsolvent such as acetone or glacial acetic acid, preferably the latter,or with an organic base such as collidine.

To prepare the 14-dehydroallopregnane-3,20-dione and14-dehydropregnane-3,20-dione derivatives of this invention,14-dehydroprogesterone is catalytically hydrogenated by treatment withat least one mole of hydrogen per mole of steroid. Suitablehydrogenation catalysts utilizable in effecting this reaction areplatinum, Raney nickel, and palladium, although any other knownhydrogenation catalyst may be employed. The reaction results in amixture of 14-dehydroallopregnane-3,20-dione andll4-dehydropregnane-3,20-dione derivatives, which can then be separatedas more fully described hereinafter in Example 4.

The 14-dehydroprogesterone of this invention is an active material whichpossesses progestation-al activity. Thus, this new steroid can beadministered instead of, and in the same manner as, progesterone in thetreatment of functional uterine bleeding and amenorrhea. The dosage forsuch administration is, of course, dependent on the relative activity ofthe new steroid and progesterone. The l4-dehydroa1lopregnane-3,20-dioneand 14-dehydropregnane-3,20dione derivatives are also new steroids whichare active asmyotrophic or protein-anabolic agents.

The following examples are illustrative of the invention (alltemperature being in centigrade):

EXAMPLE 1 1 5 (1-H ydroxyprogesterone Mesylate To a solution of 60 mg.of l5a-hydroxyprog-esterone in 4 m1. of dry pyridine is added at 0 asolution of 42 mg. of methanesulfonyl chloride in 1.3 ml. of chloroform.The mixture is allowed to remain at 0 for 18 hours and is then taken upin chloroform and ice water. After separation of the phases, theclfloroform solution is washed with dilute sulfuric acid, water, dilutesodium bicarbonate solution and again with water and finally dried oversodium sulfate. Evaporation of the solvent in vacuo leaves a crystallineresidue (about mg), which after recrystallization from ethanol afiordspure 15a-hydroxyprogesterone mesylate having the following properties,M.P. about 156 (dec.); [a] +l58 (c., 0.90 in chloroform);

A215,; 239 m (e=20,900);

A 5.90 (ZO-keto), 6.05 1, 6.22u (N-3-keto) max.

Analysis.--Calcd. for C H O S (408.48): C, 64.68; H, 7.90; S, 7.84. C,64.78; H, 7.78; S, 7.90.

EXAMPLE 2 1Sfl-Hydroxyprogesterone M esy late To a solution of 32 mg. ofISti-hydroxyprogesterone in 2 ml. of anhydrous pyridine is added asolution of 133 mg. of methanesulfonyl chloride in 4.4 ml. ofchloroform. The mixture is allowed to remain at 0 for 70 hours and isthen worked up as described in Example 1. Since 15;?-hydroxyprogesterone mesylate is extremely unstable and losesmethanesulfonic acid readily all the operations have to be carried outwith extreme care and at low temperature. The crystalline residueremaining after removal of the chloroform in vacuo is recrystallizedfrom benzenehexane taking care that the temperature never rises above23. The mesylate melts at about 1l4-116 (dec.) and has [a] |-8l (c.,0.60 in chloroform).

Analysis.-Calcd. for C H O S (408.48): S, 7.84; S, 6.84.

Attempts to recrystallize this substance at higher temperatures or fromalcohol results in elimination of methanesulfonic acid and in theformation of l4-dehydroprogesterone.

If ethanesulfonyl chloride, propanesulfonyl chloride, benzenesulfonylchloride or p-toluenesulfonyl chloride is substituted for themethanesulfonyl chloride in the procedures of Examples 1 or 2, thecorresponding ethanesulfonic acid, propanesulfonic acid, benzenesulfonicacid and p-toluenesulfonic acid esters, respectively, are formed.

EXAMPLE 3 14-Dehydr0pr0gesterone A solution of 636 mg. ofISB-hydroxyprogesterone mesylate and 1.3 g. of sodium acetate in 25 ml.of glacial acetic acid is refluxed for 50 minutes. After removal of theacetic acid in vacuo the residue is taken up in chloroform, thechloroform solution is washed with water, dilute sodium bicarbonate andagain with water and then dried over sodium sulfate. Removal of thesolvent in vacuo leaves a crystalline residue (about 461 mg.) whichafter recrystallization from acetone-hexane furnishes about 250 mg. ofl4-dehydroprogesterone. The pure substance has the following properties,M.P. about l4l143 [M 4- 132 (c., 0.9 in chloroform);

max.

Ar'zalysisr-Calcd. for C H O (312.44): C, 80.73; H, 9.03. C, 80.50; H,8.81.

An additional amount of l4-dehydroprogesterone is obtained bychromatography of the mother liquors on sulfuric acid-washed alumina,and elution of the column with a mixture of 1 vol. of benzene and 2 vol.of hexane.

Treatment of l5a-hydroxyprogesterone mesylate with sodium acetate inglacial acetic acid under the above-described conditions likewisefurnishes 14-dehydroprogesterone identical in all respects with thematerial obtained from the lSfl-mesylate.

[[n a similar manner, 15a-hydroxypr0gester0ne ethanesulfonate,ISB-hydroxyprogcsterone ethanesulfonate, 150chydroxyprogesterouepropanesulfonate, ISfi-hydroxyprogesterone propanesulfonate, 15a-hydroxyprogesterone benzenesulfonate, 15 B-hydroxyprogesteronebenzenesulfonate, l5a-hydroxyprogesterone p-toluenesulfonate and15,8-hydroxyprogesterorie p-toluencsulfonate, when subjected to thereaction of Example 3, yield l4-dehydroprogesterone.

EXAMPLE 4 14-Dehyldroallopregnane-3,20-Dione and 14-Dehydr0-pregnane-3,20-Dine To a suspension of 60 mg. of palladium on bariumsulfate catalyst in 2.5 ml. of ethyl acetate which has been pre-reducedwith hydrogen is added a solution of mg. of 14-dehydroprogesterone in1.5 ml. of ethyl acetate. Hydrogen uptake is complete after 22 minutesand amounts to 5.9 ml. equal to 1.23 moles/mole of substrate. Aftercentrifugation of the catalyst, the ethyl acetate solution is evaporatedto dryness in vacuo and the residue separated into two components byfractional crystallization from methanol. The more insoluble componentmelts at about 187192 and represents l4-dehydroallopregnane-3,20-dione.The more soluble and more abundant component representsl4-dehydropregnane-3,ZO-dione and has the following properties, M.P.about 158-160, [a] +73 (c., 0.40 in chloroform);

Ami? 5.82 (3-keto), 5.89 (20-keto) Analysis.-Calcd. for C H O C, 80.21;H, 9.62. C, 80.37; H, 9.42.

The invention may be otherwise variously embodied within the scope ofthe appended claims.

I claim:

1. A l5-(organic-sulfonyloxy)-progesterone of the general formulaReferences Cited in the file of this patent UNITED STATES PATENTS MurrayFeb. 23, 1954 Skull Feb. 22, 1955 Levin Feb. 14, 1956 Fried et al. July24, 1956

1. A 15-(ORGANIC-SULFONYLOXY)-PROGESTERONE OF THE GENERAL FORMULA